ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007
Open accessAbstract
ACMG previously developed recommendations for standards for interpretation of sequence variations. We now present the updated revised recommendations. Here, we describe six interpretative categories of sequence variations: (1) sequence variation is previously reported and is a recognized cause of the disorder; (2) sequence variation is previously unreported and is of the type which is expected to cause the disorder; (3) sequence variation is previously unreported and is of the type which may or may not be causative of the disorder; (4) sequence variation is previously unreported and is probably not causative of disease; (5) sequence variation is previously reported and is a recognized neutral variant; and (6) sequence variation is previously not known or expected to be causative of disease, but is found to be associated with a clinical presentation. We emphasize the importance of appropriate reporting of sequence variations using standardized terminology and established databases, and of clearly reporting the limitations of sequence-based testing. We discuss follow-up studies that may be used to ascertain the clinical significance of sequence variations, including the use of additional tools (such as predictive software programs) that may be useful in variant classification. As more information becomes available allowing the interpretation of a new sequence variant, it is recommended that the laboratory amend previous reports and provide updated results to the physician. The ACMG strongly recommends that the clinical and technical validation of sequence variation detection be performed in a CLIA-approved laboratory and interpreted by a board-certified clinical molecular geneticist or equivalent.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The previous ACMG recommendations provided interpretative categories of sequence variants and an algorithm for interpretation, but did not provide defined terms or detailed variant classification guidance.
“While the previous ACMG recommendations provided interpretative categories of sequence variants and an algorithm for interpretation, the recommendations did not provide defined terms or detailed variant classification guidance. 1”
From Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (2015) · cites this paper as [1]
Section I, “Interpretative Categories and Definitions of Sequence Variations” (page not supplied), sets out six categories and gives specific examples for classifying variants, including stop-codon, splice-junction, and missense changes. The paper also refers to applying algorithms (Fig. 1). Thus it supports the categories-and-algorithm portion but contradicts the assertion that these recommendations provided no definitions or detailed classification guidance. (LLM, conf=0.83)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe ACMG previously developed guidance for the interpretation of sequence variants.
“The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
No references could be resolved yet.
Research works printed but not linked: 11
- [1]1. Kazazian, H.H. ∙ Boehm, C.D. ∙ Seltzer, W.K. ACMG recommendation for standards for interpretation of sequence variations 10.1097/00125817-200009000-00009 Genet Med. 2000; 2:302-303 Google Scholar · DOI
- [3]3. db SNP at the National Center for Biotechnology Information in Bethesda, Maryland, 1988. Available at: www.ncbi.nlm.nih.gov/sites/entrez?db=snp Accessed November 26, 2007. Google Scholar
- [4]4. Fitze, G. ∙ Schreiber, M. ∙ Kuhlisch, E. ... Association of RET proto-oncogene codon 45 with Hirschsprung Disease 1:CAS:528:DyaK1MXns1Cksr8%3D 10.1086/302618 Am J Hum Genet. 1999; 65:1469-1473 Google Scholar · DOI
- [5]5. American College of Medical Genetics standards and guidelines for clinical genetics laboratories, 2007 edition. Available at: http://www.acmg.net/AM/Template.cfm?Section=Laboratory_Standards_and_Guidelines&Template=/CM/HTMLDisplay.cfm&ContentID=2009 Accessed November 26, 2007. Google Scholar
- [7]7. den Dunnen, J.T. ∙ Antonarakis, S.E. Nomenclature for the description of human sequence variations 1:CAS:528:DC%2BD3MXltlGqtLw%3D 10.1007/s004390100505 Hum Genet. 2001; 109:121-124 Google Scholar · DOI
- [8]8. den Dunnen, J.T. ∙ Antonarakis, S.E. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion 1:CAS:528:DC%2BD3cXltV2htw%3D%3D 10.1002/(SICI)1098-1004(200001)15 Hum Mutat. 2000; 15:7-12 :1<7::AID-HUMU4>3.0.CO;2-N Google Scholar · DOI
- [10]10. NCBI refseq database at the National Center for Biotechnology Information in Bethesda, Maryland. Available at: http://www.ncbi.nlm.nih.gov/RefSeq/ Accessed November 28, 2007. Google Scholar
- [13]13. Grantham, R. Amino acid difference formula to help explain protein evolution 1:CAS:528:DyaE2cXlsVOiuro%3D 10.1126/science.185.4154.862 Science. 1974; 185:862-864 Google Scholar · DOI
- [14]14. Ng, P.C. ∙ Henikoff, S. SIFT: predicting amino acid changes that affect protein function 1:CAS:528:DC%2BD3sXltVWjs7s%3D 10.1093/nar/gkg509 Nucleic Acids Res. 2003; 31:3812-3814 Google Scholar · DOI
- [16]16. Berezin, C. ∙ Glaser, F. ∙ Rosenberg, Y. ... ConSeq: the identification of functionally and structurally important residues in protein sequences 1:CAS:528:DC%2BD2cXkt1Srtbw%3D 10.1093/bioinformatics/bth070 Bioinformatics. 2004; 20:1322-1324 Google Scholar · DOI
- [19]19. Social, Ethical and Legal Issues Committee ACMG policy statement: duty to recontact 10.1097/00125817-199905000-00010 Genet Med. 1999; 1:171-172 Google Scholar · DOI
Cited by
Sorted by citations
Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., et al. (2015) · Genetics in Medicine · doi:10.1038/gim.2015.30 · Cited by 32,594 · see citing works
Self-citationClinVar: public archive of relationships among sequence variation and human phenotype
Landrum, M. J., Lee, J. M., Riley, G. R., Jang, W., Rubinstein, W. S., Church, D. M., & Maglott, D. R. (2014) · Nucleic Acids Research · doi:10.1093/nar/gkt1113 · Cited by 3,516 · see citing works
Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline
Lenders, J. W. M., Duh, Q.-Y., Eisenhofer, G., Gimenez-Roqueplo, A.-P., Grebe, S. K. G., Murad, M. H., Naruse, M., Pacak, K., & Young, W. F. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-1498 · Cited by 2,827 · see citing works
Molecular Findings Among Patients Referred for Clinical Whole-Exome Sequencing
Yang, Y., Muzny, D. M., Xia, F., Niu, Z., Person, R., Ding, Y., Ward, P., Braxton, A., Wang, M., Buhay, C., et al. (2014) · JAMA · doi:10.1001/jama.2014.14601 · Cited by 1,360 · see citing works
Guidelines for investigating causality of sequence variants in human disease
MacArthur, D. G., Manolio, T. A., Dimmock, D. P., Rehm, H. L., Shendure, J., Abecasis, G. R., Adams, D. R., Altman, R. B., Antonarakis, S. E., Ashley, E. A., et al. (2014) · Nature · doi:10.1038/nature13127 · Cited by 1,224 · see citing works
Ashley, E. A. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2016.86 · Cited by 1,116 · see citing works
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder
C Yuen, R. K., Merico, D., Bookman, M., L Howe, J., Thiruvahindrapuram, B., Patel, R. V., Whitney, J., Deflaux, N., Bingham, J., Wang, Z., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4524 · Cited by 844 · see citing works
Whole-genome sequencing of quartet families with autism spectrum disorder
Yuen, R. K. C., Thiruvahindrapuram, B., Merico, D., Walker, S., Tammimies, K., Hoang, N., Chrysler, C., Nalpathamkalam, T., Pellecchia, G., Liu, Y., et al. (2015) · Nature Medicine · doi:10.1038/nm.3792 · Cited by 514 · see citing works
Functional precision cancer medicine—moving beyond pure genomics
Letai, A. (2017) · Nature Medicine · doi:10.1038/nm.4389 · Cited by 366 · see citing works
BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study
Zhen, D. B., Rabe, K. G., Gallinger, S., Syngal, S., Schwartz, A. G., Goggins, M. G., Hruban, R. H., Cote, M. L., McWilliams, R. R., Roberts, N. J., et al. (2015) · Genetics in Medicine · doi:10.1038/gim.2014.153 · Cited by 295 · see citing works
Wang, X., Wang, H., Sun, V., Tuan, H.-F., Keser, V., Wang, K., Ren, H., Lopez, I., Zaneveld, J. E., Siddiqui, S., et al. (2013) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2013-101558 · Cited by 159 · see citing works
Morales, A., Kinnamon, D. D., Jordan, E., Platt, J., Vatta, M., Dorschner, M. O., Starkey, C. A., Mead, J. O., Ai, T., Burke, W., et al. (2020) · Circulation: Genomic and Precision Medicine · doi:10.1161/circgen.119.002480 · Cited by 114 · see citing works
Baumgartner-Parzer, S., Witsch-Baumgartner, M., & Hoeppner, W. (2020) · European Journal of Human Genetics · doi:10.1038/s41431-020-0653-5 · Cited by 110 · see citing works
Mutations in <i>HECW2</i> are associated with intellectual disability and epilepsy
Halvardson, J., Zhao, J. J., Zaghlool, A., Wentzel, C., Georgii-Hemming, P., Månsson, E., Ederth Sävmarker, H., Brandberg, G., Soussi Zander, C., Thuresson, A.-C., et al. (2016) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2016-103814 · Cited by 71 · see citing works
- Authors
- Richards, C. S., Bale, S., Bellissimo, D. B., Das, S., Grody, W. W., Hegde, M. R., Lyon, E., & Ward, B. E.
- Affiliations
- Oregon Health & Science University (US)
- Versiti Blood Center of Wisconsin (US)
- University of Chicago (US)
- University of California, Los Angeles (US)
- Emory University (US)
- University of Utah (US)
- Genomic Health (United States) (US)
- Corresponding author
- Richards, C. Sue
- Venue
- Genetics in Medicine
- Publisher
- Elsevier BV
- Published
- 2008-04
- Volume
- 10
- Issue
- 4
- Pages
- 294-300
- ISSN
- 1098-3600 (ISSN-L)
- OpenAlex
- W2003873813
- Cited by
- 832
- References
- 0
- Citations by year
- 2026: 14 · 2025: 28 · 2024: 34 · 2023: 35 · 2022: 51 · 2021: 56 · 2020: 45 · 2019: 44 · 2018: 55 · 2017: 58 · 2016: 76 · 2015: 97 · 2014: 84 · 2013: 55 · 2012: 36
- FWCI
- 12.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Genetics in Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Medicine › Physiology › Clinical Laboratory Practices and Quality Control
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Screening and Diagnostics
- Keywords
- ACMG guidelines, variant interpretation, variant reporting, clinical significance, genetic testing limitations, variant database, follow-up study
- MeSH terms
- Base Sequence, Genetics, Medical, Humans, Terminology as Topic, Research Design, Genetic Variation, Databases, Genetic
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
